Peroxisome proliferator-activated receptor-γ agonists prevent in vivo remodeling of human artery induced by alloreactive T cells

Circulation. 2011 Jul 12;124(2):196-205. doi: 10.1161/CIRCULATIONAHA.110.015396. Epub 2011 Jun 20.

Abstract

Background: Ligands activating the transcription factor peroxisome proliferator-activated receptor-γ (PPARγ) have antiinflammatory effects. Vascular rejection induced by allogeneic T cells can be responsible for acute and chronic graft loss. Studies in rodents suggest that PPARγ agonists may inhibit graft vascular rejection, but human T-cell responses to allogeneic vascular cells differ from those in rodents, and the effects of PPARγ in human transplantation are unknown.

Methods and results: We tested the effects of PPARγ agonists on human vascular graft rejection using a model in which human artery is interposed into the abdominal aorta of immunodeficient mice, followed by adoptive transfer of allogeneic (to the artery donor) human peripheral blood mononuclear cells. Interferon-γ-dependent rejection ensues within 4 weeks, characterized by intimal thickening, T-cell infiltrates, and vascular cell activation, a response resembling clinical intimal arteritis. The PPARγ agonists 15-deoxy-prostaglandin-J(2), ciglitazone, and pioglitazone reduced intimal expansion, intimal infiltration of CD45RO(+) memory T cells, and plasma levels of inflammatory cytokines. The PPARγ antagonist GW9662 reversed the protective effects of PPARγ agonists, confirming the involvement of PPARγ-mediated pathways. In vitro, pioglitazone inhibited both alloantigen-induced proliferation and superantigen-induced transendothelial migration of memory T cells, indicating the potential mechanisms of PPARγ effects.

Conclusion: Our results suggest that PPARγ agonists inhibit allogeneic human memory T cell responses and may be useful for the treatment of vascular graft rejection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Anilides / pharmacology
  • Animals
  • Arteries / immunology*
  • Arteries / pathology
  • Arteries / transplantation*
  • Cell Movement / drug effects
  • Cell Movement / immunology
  • Cell Proliferation / drug effects
  • Cytokines / immunology
  • Graft Rejection / drug therapy
  • Graft Rejection / immunology*
  • Graft Rejection / pathology
  • Humans
  • Hypoglycemic Agents / pharmacology*
  • Immunologic Memory / drug effects
  • Immunologic Memory / immunology
  • Isoantigens / immunology
  • Mice
  • Mice, SCID
  • PPAR gamma / agonists*
  • PPAR gamma / antagonists & inhibitors
  • PPAR gamma / immunology
  • Pioglitazone
  • Prostaglandin D2 / analogs & derivatives*
  • Prostaglandin D2 / pharmacology
  • Superantigens / pharmacology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / pathology
  • T-Lymphocytes / transplantation
  • Thiazolidinediones / pharmacology*
  • Transplantation, Heterologous
  • Transplantation, Homologous

Substances

  • 15-deoxyprostaglandin J2
  • 2-chloro-5-nitrobenzanilide
  • Anilides
  • Cytokines
  • Hypoglycemic Agents
  • Isoantigens
  • PPAR gamma
  • Superantigens
  • Thiazolidinediones
  • Prostaglandin D2
  • ciglitazone
  • Pioglitazone